Activating mutations in JAK2 and in MPL are present in the majority of patients with the myeloproliferative neoplasms (MPN) essential thrombocytosis (ET) and primary myelofibrosis (PMF). The identification of MPL mutations in ET and PMF demonstrates that constitutive activation of JAK2 by somatic mutations in hematopoietic cytokine receptors is an important pathogenic event in JAK2V617F-negative MPN. Expression of MPL mutations results in constitutive activation of JAK-STAT signaling and confers in vivo a myeloproliferative phenotype notable for thrombocytosis, extramedullary hematopoiesis, and myelofibrosis. Despite these important insights, the specific signaling pathways activated by different MPL and JAK2 mutations that contribute to transformation have not been determined. The reason for the relative lack of efficacy of efficacy of JAK2 inhibitors in the treatment of MPN is not understood and potential mechanisms of resistance to JAK2 inhibitors in ET and PMF have not been fully elucidated. The goals of this project are to understand how aberrant signaling leads to the development of ET and PMF and to work towards the development of novel therapies for patients with these MPN. We will analyze signaling in cell lines expressing MPL/JAK2 alleles, mouse MPN models, and primary MPN samples, and use genetic studies to assess the role and requirement for STAT3 and STAT5 signaling in ET/MF pathogenesis. We will also investigate the basis for JAK2 inhibitor resistance, and assess the requirement for JAK2 in MPL mutant mediated transformation. The long term goal of this project is to improve our understanding of the pathogenesis of ET and PMF and to work towards developing more effective therapies for patients with these MPN.